Aug 2026· European journal of medicinal chemistry· Vol 319, pp.
119219
· 0 citations· 45 references
Medicine
TL;DR
Compound 4v emerged as a leading candidate, showing EGFR kinase inhibitory activity comparable to Erlotinib, and computational analysis of 4v and EGFR molecular binding suggests that it serves as a superior binder to the inactive EGFR conformation.
Abstract
Chromone derivatives are acknowledged as a privileged scaffold, recognized for their diverse pharmacological activities, including anti-cancer properties, although comprehensive investigations in this domain have been limited. This research addresses the design, synthesis, and biological evaluation of a new series of C-2 anilinated chromone derivatives. Compounds 4v, 4x, and 4y exhibited significant in vitro cytotoxicity against hepatocellular carcinoma (HepG-2) and breast adenocarcinoma (MCF-7) cell lines. Importantly, all three compounds exceeded the cytotoxicity of Erlotinib against MCF-7 and HepG-2 cancer cells. Compound 4v emerged as a leading candidate, showing EGFR kinase inhibitory activity (IC50 = 60.7 nM) comparable to Erlotinib. It prompted cellular apoptosis and initiated cell cycle arrest at the G2/M phase. Mechanistic studies indicated that compound 4v upregulated essential pro-apoptotic factors, including P53, Bax, PUMA, and caspases-7, -8, and -9. In vivo experiments utilizing a xenograft SEC model demonstrated similar tumor growth inhibition and volume reduction between 4v and erlotinib. Computational analysis of 4v and EGFR molecular binding, considering both the active (PDB ID: 1M17) and inactive (PDB ID: 4HJO) forms, suggests that it serves as a superior binder to the inactive EGFR conformation. These results collectively underscore C-2 anilinated chromone derivatives, particularly 4v as a lead, as promising candidates for the advancement of effective anti-cancer therapeutics.
A rational pharmacophore-guided strategy was employed to design and synthesize a series of novel coumarin derivatives as potential dual cyclin-dependent kinase 6 (CDK6) and vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. Following structural characterization, the synthesized compounds were evaluated for their anticancer activity against MCF-7, MDA-MB-231, HepG-2, and HCT-116 cancer cell lines, together with normal WI-38 and WISH cells. Among the tested derivatives, compound 7e exhibited the highest potency, with IC50 values ranging from 3.80 to 6.35 µM, while demonstrating superior selectivity toward cancer cells compared with sorafenib. Enzymatic assays confirmed potent dual inhibition of VEGFR-2 (IC50 = 0.3905 µM) and CDK6 (IC50 = 0.3380 µM). Mechanistic studies revealed that compound 7e induced significant apoptosis, promoted S-phase cell cycle arrest, and effectively inhibited cell migration in HCT-116 cells. Computational studies, including molecular docking, molecular dynamics simulations, and binding free energy calculations, supported its stable interactions with both kinase targets. Furthermore, in silico ADMET analysis predicted favorable pharmacokinetic and safety profiles. Collectively, these findings identified compound 7e as a promising dual VEGFR-2/CDK6 inhibitor with potent and selective anticancer activity, warranting further preclinical investigation.
Hazem Elkady, Walid E. Elgammal, I. Eissa et al.· RSC Advances· 0 citations
Histone deacetylase (HDAC) inhibitors are important epigenetic anticancer agents that regulate gene expression, induce cell cycle arrest, and promote apoptosis. In this study, a novel series of 2-oxoindoline-capped hydroxamic acids was designed, synthesized and evaluated for their capacity to inhibit histone deacetylases and suppress cancer cell proliferation. The screening panel incorporated multiple cancer models spanning different organ systems, including colorectal adenocarcinoma (SW620, HCT116), triple-negative breast cancer (MDA-MB-231), non-small cell lung carcinoma (A549), and prostate cancer (PC-3). Comparative assessment against non-transformed fibroblasts (MRC-5) enabled evaluation of selectivity and tolerability profiles. Several derivatives exhibited potent HDAC inhibition at submicromolar concentrations, with compounds 7c, 10b, and 10c showing stronger activity than the reference inhibitor SAHA. Among them, compound 10c demonstrated broad antiproliferative effects while maintaining relatively low toxicity toward normal cells. Mechanistic investigations revealed that 10c induced S-phase cell cycle arrest and promoted apoptosis in SW620 colorectal cancer cells. Molecular docking studies against multiple HDAC isoforms supported the experimental findings by revealing favorable zinc coordination and key interactions within the catalytic pocket. To further elucidate the binding behavior and dynamic features of the most active derivatives, molecular dynamics simulations were performed for HDAC complexes with 7c, 10b, and 10c. The simulations revealed stable protein–ligand interactions without perturbation of the overall protein structure, while highlighting distinct binding dynamics among the compounds, with 10c exhibiting the highest binding persistence, followed by 7c and 10b. In addition, in silico ADME and toxicity predictions were carried out for compound 10c as a representative highly active derivative, indicating acceptable drug-like properties and a favorable safety profile. Overall, 2-oxoindoline-based hydroxamic acids, particularly those bearing extended alkyl linkers, represent promising scaffolds for further development of HDAC-targeted anticancer agents.
Huong Thi Lan Tran, Hwa Kyung Kim, Thai Anh Nguyen et al.· RSC Advances· 0 citations
Cardiotoxicity remains a major limitation of current anticancer therapies, highlighting the need for agents that combine antitumor efficacy with intrinsic cardiac safety. Phenotypic screening of a pyrimidine-based compound library identified compound 9v as a potent anti-prostate cancer candidate with dual biological functions. Compound 9v inhibited PC-3 cell proliferation with an IC₅₀ of 3.96 ± 0.18 μM, outperforming 5-fluorouracil, and markedly suppressed colony formation and migration while inducing apoptosis. Mechanistic studies showed that 9v activated the mitochondrial apoptotic pathway by increasing Bax, cleaved caspase-9, and cleaved caspase-3 levels while reducing Bcl-2 expression. Remarkably, 9v exerted bidirectional regulation of ROS homeostasis, promoting ROS accumulation in PC-3 cells but suppressing oxidative stress in H9C2 cardiomyocytes under H₂O₂ challenge. In addition, 9v exhibited weak cytotoxicity toward normal prostate stromal cells, no obvious acute toxicity in mice, and no detectable cardiotoxicity in vitro. Moreover, it exhibited protective effects against oxidative injury in cardiomyocytes, as demonstrated by increased cell viability and decreased LDH and cTnT release. Taken together, these results identify 9v as a promising lead compound with both anti-prostate cancer activity and cardioprotective potential in an in vitro oxidative stress model, providing a basis for the development of multifunctional anticancer agents with improved cardiovascular safety.
Yaquan Cao, Ya-Xi Wu, Yunfei Li et al.· Bioorganic & Medicinal Chemi...· 0 citations
To identify targeted cytotoxic agents for the treatment of non-small cell lung cancer (NSCLC), novel thiazolyl hydrazones (2a-t) were synthesized and evaluated for their cytotoxicity toward A549 human lung adenocarcinoma and L929 mouse embryonic fibroblast cells. Among these compounds, compound 2b exhibited the highest cytotoxic activity against A549 cells (IC50= 6.10 µM), followed by compounds 2g, 2k, 2r, 2f, 2o, 2e, 2s, and 2h, all of which were more potent than erlotinib (IC50 = 77.35 μM). In vitro mechanistic assays were conducted to assess their effects on apoptosis, cell cycle, epidermal growth factor receptor (EGFR), Akt, and signal transducer and activator of transcription 3 (STAT3). Flow cytometry analyses revealed that these agents induced apoptosis and G0/G1 cell cycle arrest, indicating that their cytotoxic effects are mediated through these mechanisms. Compound 2f was identified as the most promising compound, exhibiting selective cytotoxicity mediated by the concurrent inhibition of EGFR, Akt, and STAT3, with greater inhibitory potency toward EGFR and STAT3 relative to the EGFR TKI erlotinib and the STAT3 inhibitor C188-9. Compound 2e emerged as a potent dual EGFR/STAT3 inhibitor, exerting EGFR inhibitory activity comparable to that of erlotinib while exhibiting superior STAT3 inhibitory activity relative to C188-9. Compound 2b showed the highest cytotoxic potency against A549 cells, primarily through EGFR inhibition, with 8.3-fold greater activity than erlotinib. Compound 2r was identified as the most potent STAT3 inhibitor, exerting 10.8-fold higher activity than C188-9. These findings highlight the potential of thiazolyl hydrazones as targeted therapeutic agents, warranting further investigations for NSCLC treatment.
M. Altıntop, Ipek Ertorun, G. Çiftçi et al.· Bioorganic chemistry (Print)· 0 citations
Among the synthesized compounds, PBc1 exhibited the greatest in vitro antiproliferative activity against both MDA-MB-231 and SK-OV-3 cell lines, suggesting that PBc1 is a promising compound for further biological and mechanistic investigation.
Prachita Gauns Dessai, Parixit J. Bhandurge, C. Nazareth et al.· Journal of the Iranian Chemi...· 0 citations
Phenotypic drug discovery enables the identification of compounds with novel mechanisms of action and context-dependent biological activities that may not emerge from target-based approaches. Through high-content phenotypic screening, we identified the (E)-6-(2-((1H-indol-3-yl)methylene)hydrazineyl)-N,N-diethylpyrimidin-4-amine (IMHDPA) scaffold as a potent and highly selective inhibitor of HeLa cell proliferation. To further explore this scaffold, a library of 70 analogues was synthesized, and structure-activity relationship studies revealed stringent structural requirements for maintaining cellular potency and selectivity. Among them, compound 39 emerged as the most active derivative, exhibiting a GI50 value of 2.96 nM against HeLa cells and an exceptional selectivity index exceeding 16,000-fold across a panel of 15 cell lines. Compound 39 suppressed colony formation, migration, invasion, and spheroid growth, while inducing pronounced morphological alterations in HeLa cells. Mechanistic investigations indicated that its antiproliferative activity was associated with autophagy activation rather than apoptosis, necrosis, ferroptosis, or reactive oxygen species accumulation. Integrated transcriptomic and proteomic analyses implicated perturbation of cholesterol metabolism and inhibition of mTORC1 signaling as potential upstream events linked to autophagy induction. Collectively, these findings establish IMHDPA derivatives as promising chemical probes for investigating the molecular basis of context-dependent autophagy-associated cytotoxicity and support future efforts aimed at elucidating the molecular determinants underlying this selective phenotype.
Pengfei Wang, Han Wu, Jiaming Zhang et al.· European journal of medicina...· 0 citations
